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by Shannon Fischer and Shabana Sayed

In the last five years, the emergence of commercial time-lapse imaging devices, such as the EmbryoScope, have spurred a new study of human embryo behavior in reproductive medicine. Currently, clinics worldwide are investigating ways to use such tools to better analyze embryo potential and maximize the odds of pregnancy. Klinikk Hausken was the first clinic in Norway to begin experimenting with the EmbryoScope in 2010, and it has since developed an algorithm using time-lapse parameters that has allowed them to achieve a relative increase in live birth rates per embryo transferred by 24%. Research is ongoing to explore the implications and molecular underpinnings of newly observed embryo behaviors throughout the reproductive field.

Klinikk Hausken is Norway’s largest private in vitro fertilization (IVF) clinic, with branches located in both Haugesund and Bergen. Its patients are typically last-resort, having already failed to achieve pregnancy via the three rounds of government funded IVF attempts. As a result, the clinic maintains a focus on innovative treatments and technologies designed to maximize success rates for difficult cases.

In 2010, Klinikk Hausken obtained its first EmbryoScope—a Danish-made incubator with an inbuilt microscope and software system that allows for the simultaneous culture and serial imaging of up to 72 embryos at programmed intervals (e.g., every 10 minutes), with manual annotation and analysis support. The device is one of several systems, including the Eeva and Primo Vision, which have appeared on the IVF market recently. All rely on the relatively novel concept that the history of an embryo’s development is at least as important, if not far more, than its appearance at the time it is selected for transfer back into the mother’s uterus. This is in contrast to the traditional assessment method in which embryos are judged in short, static observations once or twice daily until transfer.

Video 1: 3 Cells to 2 Cells

Video 2: 1 Cell to 3 Direct

Upon receiving its EmbryoScope, Klinikk Hausken, led by IVF laboratory director Shabana Sayed, began a series of in-house trials to confirm the safety of the culture and then piece out key embryo behaviors they could correlate with subsequent success or failure. Their resulting assessment algorithm accounts for several types of parameters: first, traditional analysis that assesses whether the embryo conforms to the classic health measures. Next, the algorithm applies de-selection parameters—gross behavioral anomalies that would ordinarily go unseen. Such measures include reverse cleavage (Video 1: 3 cells to 2 cells), in which an embryo progresses backwards after a division, direct cleavage (Video 2: 1 cell to 3 direct), in which embryos skip over key divisions, going straight from one cell to three without the appropriate two-cell stage, and nuclear errors, in which cells in an embryo may have no nucleus, too many nuclei, or misshapen nuclei (Videos 3, 4: binucleation, multinucleation, micronucleation), all of which seems to be indicative of genetic or developmental errors and generally bode poorly for the cells’ ultimate success.

Video 3: Binucleation, Multinucleation, Micronucleation

Video 4: Binucleation, Multinucleation, Micronucleation

More recently, the clinic has folded in a third layer, encompassing embryo morphokinetics. These are the more subtle distinctions that appear to differentiate average embryos from those most likely to produce a successful pregnancy, and include factors such as the amount of time it takes for an embryo to successfully reach two cells, then three and four cells, and how synchronously such divisions occur (Video 5: embryo selection based on morphokinetics). Since applying this algorithm to their clinic, Klinikk Hausken has achieved a relative increase in their live birth rates per embryo transferred by 24%; it now has a total of four EmbryoScopes, which it applies across the board to all patients without cost increase.

Video 5: Embryo selection based on Morphokinetics

Time-lapse in human embryology remains a very young and still controversial trend. As part of the European Society of Human Reproduction and Embryology (ESHRE) Time-Lapse User Group, Sayed co-authored a recent Human Reproduction article calling for a consensus in annotation practices field-wide to tame mixed results in the literature that may stem in part from uneven terminology and assessment. New opportunities exist for scientists to continue dissecting newly observe embryo phenomenon and their implications. The Norway group is currently exploring the clinical meaning of very early developmental events it has noticed, such as the synchrony with which the parental nuclei merge and fade; elsewhere, others have begun to tie morphokinetics to genetic, epigenetic, and metabolic activities that may fill the many gaps that remain in science’s understanding of humans’ earliest development.

For More Information

1. Klinikk Hausken
2. EmbryoScope® Time-Lapse System
3. The Eeva™ Test from Auxogyn
4. Primo Vision Time-Lapse Embryo Monitoring System
5. M. Meseguer, J. Herrero, A. Tejera, K. M. Hilligsøe, N. B. Ramsing, and J. Remohí, “The use of morphokinetics as a predictor of embryo implantation,” Human Reprod., vol. 26, no. 10, pp. 2658-71, 2011.
6. H. N. Ciray, A. Campbell, I. E. Agerholm, J. Aguilar, S. Chamayou, M. Esbert, and S. Sayed, “Time-Lapse User Group. Proposed guidelines on the nomenclature and annotation of dynamic human embryo monitoring by a time-lapse user group,” Human Reprod., vol. 29, no. 12, pp. 2650-60, 2014.
7. C. C. Wong, K. E. Loewke, N. L. Bossert, B. Behr, C. J. De Jonge, T. M. Baer, and R. A. Reijo Pera. “Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage,” Nature Biotechnol., vol. 28, no.10, pp. 1115-21, 2010.
8. A. Campbell, S. Fishel, N. Bowman, S. Duffy, M. Sedler, and S. Thornton, “Retrospective analysis of outcomes after IVF using an aneuploidy risk model derived from time-lapse imaging without PGS,” Reprod. Biomed Online., vol. 27, no. 2, pp. 140-6, 2013.
9. Y. S. Lee, G. A. Thouas, and D. K. Gardner, “Developmental kinetics of cleavage stage mouse embryos are related to their subsequent carbohydrate and amino acid utilization at the blastocyst stage,” Human Reprod., vol. 30, no. 3, pp. 543-52, 2015.

Contributors

Shannon Fischer is a freelance science writer living in Boston, Massachusetts. Read more

Shabana Sayed is a ESHRE certified Senior clinical Embryologist and IVF Laboratory Director at Klinikk Hausken in Norway. Her primary areas of expertise are within embryo selection and optimization of laboratory procedures for IVF.
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